The T cell receptor (TcR) repertoire to encephalitogenic epitopes of myelin basic protein (MBP), the most potent inducer of the autoimmune disease experimental allergic encephalomyelitis (EAE) has been shown to be highly delimited in the use of alpha and beta chains. In fact, the preponderant use of Vbeta8.2 and Valpha2 in combination can be said to characterize the autoimmune response in this disease model of multiple sclerosis. Recent results in the area of experimental encephalomyelitis raise the possibility that T cell receptor peptides derived from single chains of the encephalitogenic TcR, the alpha and beta chains, may play a regulatory role in the autoimmune response generated by encephalomyelitis-inducing T cell. This is an important result with interesting therapeutic implications. Our laboratory, using the Lewis rat model of EAE, has found that immunization with TcR peptides from autoreactive encephalitogenic T cell clones enhanced autoimmunity. Thus, we found early onset of EAE, a more severe disease state, and chronic symptoms of disease in the absence, surprisingly, of a TcR peptide-specific T cell or antibody response. Interestingly, we have also identified a separate colony of Lewis rats which can generate a T cell response to TcR peptide but shows no enhancement of EAE. This proposal will: 1) examine these two colonies of rats for changes in their TcR repertoire and their responsiveness to MBP and TcR peptide after immunization with TcR peptide; and 2) study the TcR peptide-specific T cells for their antigen specificity, MHC restriction, TcR gene usage, and function. We have recently found that Lewis rats, recovered from MBP-induced EAE, respond to a soluble Vbeta8+ beta chain but do not respond to the TcR peptides which we found caused enhancement of disease. We will determine if these cells are involved in down regulation and what determinants they see on the TcR.